Deletion of hensin/DMBT1 blocks conversion of β- To α-intercalated cells and induces distal renal tubular acidosis

Xiao Bo Gao, Dominique Eladari, Francoise Leviel, Ben Yi Tew, Cristina Miró-Julià, Faisal Cheema, Lance Miller, Raoul Nelson, Teodor G. Pǎunescu, Mary McKee, Dennis Brown, Qais Al-Awqati

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72 Scopus citations


Acid-base transport in the renal collecting tubule is mediated by two canonical cell types: the β-intercalated cell secretes HCO3 by an apical Cl:HCO3 named pendrin and a basolateral vacuolar (V)- ATPase. Acid secretion is mediated by the α-intercalated cell, which has an apical V-ATPase and a basolateral Cl:HCO3 exchanger (kAE1). We previously suggested that the β-cell converts to the α-cell in response to acid feeding, a process that depended on the secretion and deposition of an extracellular matrix protein termed hensin (DMBT1). Here, we show that deletion of hensin from intercalated cells results in the absence of typical α-intercalated cells and the consequent development of complete distal renal tubular acidosis (dRTA). Essentially all of the intercalated cells in the cortex of the mutant mice are canonical β-type cells, with apical pendrin and basolateral or diffuse/bipolar V-ATPase. In the medulla, however, a previously undescribed cell type has been uncovered, which resembles the cortical β-intercalated cell in ultrastructure, but does not express pendrin. Polymerization and deposition of hensin (in response to acidosis) requires the activation of β1 integrin, and deletion of this gene from the intercalated cell caused a phenotype that was identical to the deletion of hensin itself, supporting its critical role in hensin function. Because previous studies suggested that the conversion of β- toα-intercalated cells is a manifestation of terminal differentiation, the present results demonstrate that this differentiation proceeds from HCO3 secreting to acid secreting phenotypes, a process that requires deposition of hensin in the ECM.

Original languageEnglish (US)
Pages (from-to)21872-21877
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Issue number50
StatePublished - Dec 14 2010
Externally publishedYes

ASJC Scopus subject areas

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